PROJECT SUMMARY/ABSTRACT: Rapid control of emerging and re-emerging pathogens is essential to reduce transmission, morbidity and cost. Sexually transmitted diseases (STDs) ? which disproportionately affect low-income individuals, racial and ethnic minority groups, and women ? place a tremendous burden on the health of the public, as these infections are associated with increased risks of cancer, infertility and HIV. The ongoing, high level of STD transmission suggests that if a novel STD pathogen emerged, it could spread efficiently through established sexual networks. Among male STD patients in Columbus Ohio, we have identified an ongoing outbreak of urethritis caused by a distinct, novel clade of non-groupable Neisseria meningitidis (Nm) belonging to the pathogenic sequence type (ST)-11 clonal complex. Since January 2015, 20% of infections initially thought to be caused by the endemic STD pathogen Neisseria gonorrhoeae (Ng, the cause of gonorrhea) were ultimately determined to be caused by Nm. Nm is a Gram-negative diplococcus that normally colonizes the oropharynx (OP). Whereas Nm has been reported as an occasional urogenital pathogen for decades, the incidence of Nm urogenital disease is very low and suggests that sexual transmission of this pathogen is typically inefficient. However, preliminary analyses of urethral isolates from the Columbus outbreak reveal important genotypic and phenotypic changes in this Nm clade that may contribute to enhanced survival in the urogenital tract and sexual transmission. The proposed project has two aims. Aim 1 will define the clinical epidemiology of this distinct, novel Nm clade among STD clinic patients. At the same clinic where the outbreak was detected, we will screen all adult patients for urogenital Nm infection over a two-year period. Those reporting recent receptive anal or oral sex will also be screened for rectal and OP Nm infection, respectively. Patients infected with the outbreak Nm clade (index cases) and their Nm-infected and Nm-uninfected sex partners will be followed monthly for six months. All participants will provide detailed sexual behavior data and undergo monthly Nm screening at multiple anatomical sites. We will elucidate who is infected, how and where they are infected, and the spectrum of symptoms they experience. We will also determine response to treatment, assess self-clearance in the absence of treatment, characterize the sexual network, and estimate both the risk of Nm acquisition by sex partners and the risk of reinfection of index cases. Aim 2 will define the molecular epidemiology and genetic characteristics of the Nm clade that is causing the Columbus outbreak. Using whole genome sequencing, we will continue to define the genomic profile of the outbreak clade, link isolates? genetic characteristics to clinical outcomes and other factors, and determine how the genotypic features of this clade have evolved over the course of the outbreak. Through innovative characterization of a pathogenic organism that appears to have acquired enhanced capacity for sexual spread, our project has great potential to impact a significant, specific public health threat.